【作者】 刘训超；

【导师】 董亮；

【作者基本信息】 山东大学 ， 内科学（专业学位）， 2014， 博士

【摘要】 研究背景慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)严重影响人们的身体健康,是许多人致死或致残的最重要疾病之一,严重影响着公共健康,到2020,COPD将会是世界上第三位致死病因,社会负担将会增至第五位。COPD以不完全可逆性气流受限为特征,肺功能逐渐下降,有效肺组织逐渐减少,生活质量逐渐下降,致死率高。COPD全球倡议(Global Initiative for Chronic Obstructive Lung Disease, GOLD)的管理策略中,包括减轻症状,避免并发症出现,减少急性发作,提高活动耐力,改善健康状况,降低死亡率。近来,基于临床证据,一些COPD相关的指南或声明指出,在COPD管理策略中,肺康复做为最有效的非药物治疗手段,已被广泛接受。研究显示,一些肺康复锻炼方法,如上肢练习、太极、瑜伽等,可缓解呼吸困难,改善肺功能,提高COPD患者生活质量。瑜伽,其含意为“一致”、“结合”或“和谐”。是一个通过提升意识,帮助人类充分发挥潜能的体系。瑜伽姿势运用古老而易于掌握的技巧,改善人们生理、心理、情感和精神方面的能力,是一种达到身体、心灵与精神和谐统一的运动方式,包括调身的体位法、调息的呼吸法、调心的冥想法等,以达至身心的合一。瑜伽可以健身、健美形体、缓解精神压力、锻炼柔韧性,在西方世界中变得流行。研究显示,瑜伽练习可使一些疾病患者明显受益,如哮喘,心脏病,糖尿病,结核病,抑郁症,骨性关节炎,胸腔积液等。一些临床研究结果显示,瑜伽练习可以明显提高COPD患者肺功能。然而,这些研究资料并不系统。因此,我们通过对随机临床试验研究进行系统综述和Meta分析,来评价瑜伽练习对COPD患者肺功能及其他临床指标的影响,从而了解瑜伽练习对COPD患者肺康复中的价值。目的本研究通过对随机临床试验研究进行系统综述和Meta分析,来评价瑜伽练习对COPD患者肺功能及其他临床指标的影响,从而了解瑜伽练习对COPD患者肺康复中的价值。方法通过计算机及手工全面检索PubMed、EMBASE, the Cochrane Library, Google Scholar、 ClinicalTrials.gov databases、超星Medlink、中国全文期刊数据库、万方数据库。主要指标为第一秒用力呼气容积(forced expiratory volume in one second, FEV1)、FEV1占预计值百分比(FEV1％percentage predicted,FEV1％pred).次要指标为6分钟步行距离(6min walking distance,6MWD),动脉血氧分压(arterial oxygen tension,Pa02)及动脉血二氧化碳分压(arterial carbon diocide tension,PaC02).连续变量资料采用加权均数差(weighted mean differences, WMDs),其以95%可信区间(confidence intervals,CIs)表示。异质性大小程度用12异质性的定量分析。结果5篇文献被纳入,包括233例患者。瑜伽练习可显著提高FEV1(WMD123.57ml,95%CI4.12-243,P=0.04),FEV1％pred(WMD3.90%,95%CI2.27-5.54,P<0.00001)和6MWD (WMD38.84m,95%CI15.52-62.16,P=0.001)；瑜伽练习对PaO2(WMD1.29mmHg,95%CI-1.21-3.78,P=0-31)和PaC02(WMD-0.76mmHg,95％CI-2.06-0.53,P=0.25)没有影响。结论瑜伽练习可改善肺功能和活动耐力,可做为COPD患者肺康复治疗的一种有效方法,瑜伽练习对COPD患者肺康复的长期疗效需进一步研究。研究背景近年来,肺癌的发病率和病死率都在迅速上升。肺癌主要有小细胞肺癌(small cell lung cancer, SCLC)和非小细胞肺癌(non small cell lung carcinoma, NSCLC),小细胞肺癌一般在晚期发现,生存率远远低于非小细胞肺癌的生存率,因此,谈及小细胞肺癌,人们总是将之与死亡直接挂钩。伊立替康和顺铂方案目前已被美国国立综合癌症网络(National Comprehensive Cancer Network, NCCN)临床治疗指南定为广泛期SCLC的一线标准治疗方案。伊立替康在体内经强酸酯酶转化为7-乙基-10-羟基喜树碱,后者是一种拓扑异构酶I的抑制剂,能够抑制DNA单链断裂后的修复作用,从而干扰DNA复制和转录,产生毒性效应,而在体内,伊立替康代谢的关键酶是尿苷二磷酸葡萄糖苷酸转移酶(UGT1A1),该酶基因启动子区存在大量的TA碱基重复序列,野生型的UGT1A1为6个TA重复序列,即TA6/TA6,当其启动子区有7个TA重复学列,即UGT1A1*28,可分为两种突变型：TA7/TA7和TA6/TA7。 UGT1A1启动子区插入性突变可以降低其转录水平,因此,理论上讲,重复序列越多,基因转录表达就越少。UGT1A1家族常见的SNP共有3种,UGT1A1*1, UGT1A1*28, UGT1A1*6,而临床肿瘤报道最多的是UGT1A1*28多态性。小分子RNA (miRNA)是一类大小约为22个核苷酸的非编码单链分子,它在肿瘤发生发展过程中发挥重要作用。据报道,miRNA在肺癌中通过调控细胞周期,抑癌基因／癌基因和细胞凋亡等,调控了肺癌的发生发展。但是,在小细胞肺癌中,调控UGT1A1的1miRNAs的报道很少,因此,本研究致力于在大量小细胞肺癌患者中发现调控UGT1A1的miRNA,同时对临床样本UGT1A1*6多态性进行分析。目的1.对临床样本UGT1A1*6多态性进行分析。2.寻找小细胞肺癌患者中调控UGT1A1的miRNA。3.探索小细胞肺癌患者个体化治疗的分子靶标。方法通过定量聚合酶链反应(Polymerase Chain Reaction, PCR)检测了临床分离的138例小细胞肺癌和100例正常人群中UGT1A1和miR-143的相对表达,通过Sanger测序检测了小细胞肺癌人群和正常人群中UGT1A1多态性UGT1A1*6的分布；通过双荧光素酶报告系统确定了miR-143与UGT1A1的3’-UTR的结合,并将miR-143拟似物转染小细胞肺癌细胞株通过免疫印迹法确认了miR-143对UGT1A1的表达抑制作用。结果UGT1A1在小细胞肺癌患者体内显著低表达,miR-143显著抑制了荧光素酶的表达且miR-143在小细胞肺癌患者体内的表达与UGT1A1显著负性相关,同时UGT1A1多态性UGT1A1*6在小细胞肺癌和正常人群中的分布无统计学差异,但是其在使用了伊立替康治疗的小细胞肺癌患者体内高频率出现。结论通过检测UGT1A1*6多态性有助于指导小细胞肺癌患者伊立替康的个性化治疗,并且通过检测小细胞肺癌外周静脉血中UGT1A1基因的表达量能有效评估伊立替康对小细胞肺癌的疗效,从而指导临床用药。更多还原

【Abstract】 IntroductionChronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality and poses a major public health problem. By2020, COPD is predicted to rank as the third leading cause of death worldwide, whereas its social burden will rank fifth. COPD is characterized by irreversible airflow obstruction, a gradual decline in lung function, loss of lung tissue, reduced quality of life, and high rates of mortality. The GOLD (Global Initiative for Chronic Obstructive Lung Disease) management includes a reduction in symptoms, complications, and exacerbations, improved exercise tolerance, improved health status, and reduced mortality. Recent evidence-based clinical practice guidelines and statements have shown that pulmonary rehabilitation is widely accepted as the most effective non-pharmacotherapy in the management of COPD. Research have indicated that various exercises, such as upper extremity exercise, Tai Chi, and yoga training, can relieve dyspnea, improve lung function, and improve the quality of life of COPD patients. Yoga is a word that has come to describe a means of uniting or a method of discipline. It involves joining the body and the mind, and together they merge with the self (soul). It may also denote the union between the individual self and the transcendental self. First, the body’s organs and systems are cleansed through asanas (postures) and pranayama (controlling the breath). Along with meditation, yoga asanas and pranayama have become popular in the West, and the practice of yoga has become "westernized." Postures are taught as ends in themselves, that is, to heal an illness, reduce stress, or to look better. Yogic exercises have been shown to have positive effects on people with asthma, cardiac diseases, diabetes, tuberculosis, depressive disorders, osteoarthritis, and pleural effusion. A number of clinical trials have suggested that yoga training may improve the pulmonary function of patients with COPD, but the quality of these studies have not been evaluated systematically. Therefore, we undertook a systematic review and meta-analysis of available randomized controlled trials (RCTs) to assess the efficacy of yoga training on pulmonary function and other clinical endpoints in patients with COPD.ObjectiveTo assess the efficacy of yoga training on pulmonary function and other clinical endpoints in patients with COPD.MethodsPubMed, EMBASE, the Cochrane Library, Google Scholar, and ClinicalTrials.gov databases were searched for relevant studies. The primary outcomes were forced expiratory volume in one second (FEV1), FEV1%predicted (%pred). Secondary outcomes included6-min walking distance (6MWD), arterial oxygen tension (PaO2), and arterial carbon dioxide tension (PaC02). Weighted mean differences (WMDs) and95%confidence intervals (CIs) were calculated, and heterogeneity was assessed with the I2test.ResultsFive randomized controlled trials involving233patients fulfilled the inclusion criteria. Yoga training significantly improved FEV1(WMD:123.57ml,95%CI:4.12to243, P=0.04), FEV1%pred (WMD:3.90%,95%CI:2.27to5.54, P<0.00001), and6MWD (WMD:38.84m,95%CI:15.52to62.16, P=0.001). However, yoga training had no significant effects on PaO2(WMD:1.29mmHg,95%CI:-1.21to3.78, P=0.31) and PaCO2(WMD:-0.76mmHg,95%CI:-2.06to0.53, P=0.25).ConclusionsThe current limited evidence suggested that yoga training has a positive effect on improving lung function and exercise capacity and could be used as an adjunct pulmonary rehabilitation program in COPD patients. However, further studies are needed to substantiate our preliminary findings and to investigate the long-term effects of yoga training. IntroductionRecent years, the incidence and mortality rate of lung cancer rising rapidly. Lung cancer mainly contains small cell lung cancer and nonsmall-cell lung cancer, in which nonsmall-cell lung cancer comprises80%-85%. Small-cell lung cancer is usually observed during terminal stage of cancer, and survival rate of which is much lower that nonsmall-cell lung cancer. Therefore, small-cell lung cancer is usually associated with death. Irinotecan and cisplatin treatment of extensive stage SCLC have been identified as the standard method by NCCN guidelines. Irinotecan is biotransformed by tissue and serum carboxylesterases to7-ethyl-10-hydroxycamptothecin, which is an inhibitor of topoisomerase I enzyme. Therefore, Irinotecan could inhibite the restoration breakage of single-strand DNA and disturb DNA replication and transcription. In vivo, the critical enzyme of Irinotecan metabolism is uridine diphosphate glucuronyltransferase1A1(UGT1A1)[9]. Numerous TA repetitive sequences exist in UGT1A1gene promoter, in which6TA in Wild-type UGT1A1(TA6/TA6)[10]. A dinucleotide (TA) insertion in the (TA)6TAA element resulting in (TA)7(UGT1A1*28), which contains two mutation:TA7/TA7and TA6/TA7[11]. Insertional mutation of promoter surpresses the transcriptional level of UGT1A1gene. Therefore, The UGT1A1activityappears to be inversely related to the number of TA repeats. There are three SNP classification in UGTIAI gene family:UGTIA1*1, UGT1A1*28, UGTIA1*6, in which UGTIA1*28polymorphism attracts the clinical oncology studies. MiRNAs (microRNAs) are a class of endogenous non-coding, single-stranded small regulatory RNA molecules, which are approximately22nucleotides in length. Numous studies report that miRNA plays essential role in Lung cancer through regulating cell cycle and apoptosis and the expression of oncogenes/anti-oncogenes. However, the role of miRNAs in UGT1A1regulation is poorly understood for a long time. Therefore, this study focus on the function of miRNA on UGT1A1regulation and the UGT1A1*6polymorphism analysis in SCLC patients.Objective1. To analysis UGTIA1*6polymorphism in SCLC patients. 2. To study the function of miRNA on UGT1Al regulation in SCLC patients.3. To explore the molecular target of individualized treatment in SCLC patients.MethodsRelative expression of UGT1A1and miR-143in normal population(100cases) and small cell lung cancer patients (138cases) were detected by Real-time PCR; The distribution of UGT1A1*6gene polymorphism in normal population and small cell lung cancer patients were determinated by Sanger sequencing; The binding between miR-143and3’-UTR of UGT1A1were confirmed by Dual luciferase report system, and the inhibition effection of miR-143on UGT1A1was confirmed through immune-blot after transfecting miR-143mimics into small cell lung cancer cell line.ResultsUGT1A1expresses at a low level in small cell lung cancer patients, miR-143significantly suppresses the expression of luciferase, and the expression of miR-143is inverse related to UGT1A1in small cell lung cancer patients. Meanwhile, no significant difference of UGT1A1*6distribution was detected between normal population and small cell lung cancer patients, while UGT1A1*6occurs frequently in small cell lung cancer patients with Irinotecan treatment.ConclusionThe detection of UGT1A1*6genotypic polymorphism is beneficial to the individualized treatment of small cell lung cancer using Irinotecan. Meanwhile, the determination of UGT1A1relative expression in Peripheral venous blood of small cell lung cancer patients is in favor of the evaluation of the curative effect of Irinotecan on small cell lung cancer and further the clinical medication.更多还原